Long-term effects of amyloid-beta accumulation in human iPSC-derived astrocytes

• Background: Alzheimer's disease (AD) is a slowly progressive condition and the most common cause of dementia worldwide. The pathological changes associated with the disease are estimated to occur decades before the first clinical symptoms emerge. Although neurons have been the main research focus, astrocytes have recently gained attention because of their participation in several key cellular functions. Our previous data suggest that astrocytes engulf large amounts of aggregated amyloid-beta (Aβ), but are unable to successfully degrade the material. The intracellular accumulation is, at least initially, very stressful for the astrocytes and long-term Aβ deposits may be detrimental for their functionality. However, if the astrocytes can handle the Aβ storage it could instead be beneficial in a longer perspective, by minimizing the spread of potentially pathogenic Aβ species to neighboring cells.Methods: We aimed to evaluate the effects of long-term Aβ inclusions in astrocytes. Mature human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils and then further cultured for one week or ten weeks in Aβ-free medium. Cells from both time points were analyzed for lysosomal proteins and astrocyte reactivity markers and the medium was screened for inflammatory cytokines. In addition, the overall health of cytoplasmic organelles was investigated by immunocytochemistry and electron microscopy.Results: Long-term astrocytes displayed frequent Aβ inclusions that were contained within LAMP1 positive organelles and sustained markers associated with reactivity. Furthermore, increased levels of CCL2/MCP-1 were detected in the media from Aβ-exposed long-term cultures. Finally, Aβ accumulation induced endoplasmic reticulum and mitochondrial swelling as well as formation of pathological lipid structures in astrocytes.Conclusions: This study provides valuable information about how intracellular Aβ deposits affect astrocytes over time, and thereby contribute to the understanding of astrocytes role in AD progression.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Alzheimer’s disease

amyloid-beta

astrocytes

phagocytosis

accumulation

lysosomes

neuroinflammation

cytokines

reactivity

human iPSCs

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)